Transcutaneous neuromodulation system and methods of using same

ABSTRACT

Neuromodulation systems are described comprising a signal generator and at least one electrode. The at least one electrode can be configured to deliver a stimulation to a mammal, wherein the stimulation includes a biphasic signal and an overlapping high frequency pulse thereby inducing voluntary movement in the individual. Methods of administering the stimulation are also described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/069,590, filed Oct. 28, 2014, the entire disclosureof which is incorporated herein by reference.

This application is a continuation-in-part of U.S. patent applicationSer. No. 14/357,481, filed May 9, 2014, which is a national stage entryof International Patent Application PCT/US2012/064874, filed Nov. 13,2012, which claims priority to and benefit to U.S. Provisional PatentApplication No. 61/559,025, filed Nov. 11, 2011, the entire disclosureof each of which are incorporated herein by reference.

SUMMARY

Described herein generally are neuromodulation systems used with or on amammal (e.g., a human) having a spinal cord with at least one selecteddysfunctional spinal or neural circuit or other neurologically derivedsource of function or movement control in a portion of the subject's(e.g., mammal) body. The systems can be transcutaneous systems and caninduce voluntary movement in a mammal with a spinal cord injury.

In one embodiment, the neuromodulation systems can include: a processor;a signal generator; and at least one electrode. The electrode(s) can betranscutaneous electrodes. In other embodiments, in addition totranscutaneous electrodes, one or more implantable electrodes can beincluded in the system. In some embodiments, the processor, incooperation with the signal generator and the at least one electrode areconfigured to deliver a stimulation to a mammal, the stimulationincluding a monophasic or biphasic signal and an overlapping highfrequency pulse thereby inducing voluntary movement.

Methods of using the herein described systems are also disclosed. Themethods can include: applying a stimulation including a biphasic signaland an overlapping high frequency pulse to a mammal using atranscutaneous neuromodulation system thereby inducing the voluntarymovement. In some embodiments, the stimulation can be monopolar orbipolar.

In some embodiments, the voluntary movement is of a foot, a toe, a knee,a leg, a neck, a shoulder, an arm, a hand, a finger, a waist or acombination thereof. In other embodiments, the voluntary movementcomprises at least one of standing, stepping, a walking motor pattern,sitting down, laying down, reaching, grasping, pulling and pushing,taking a breath, chewing or swallowing.

In one embodiment, the biphasic signal is a 0.5-100 Hz signal that canbe delivered at 0.5-200 mA. The overlapping high frequency pulse can bea 10 kHz pulse or a 5 kHz pulse.

The stimulation can be applied over a cervical portion of the spinalcord or the brainstem. The delivered signal can also be appliedparaspinally over at least one of a cervical-thoracic portion, athoracic portion, a thoracic-lumbar portion, lumbar portion, alumbosacral portion and a sacral portion of the spinal cord. Furtherstill, the delivered signal is applied to a T11-T12 vertebrae.

In some embodiments, the systems can be used on or for mammals, such ashumans, having a neurodegenerative brain injury or disease. Theneurodegenerative brain injury or disease can be a brain injuryassociated with a condition selected from Parkinson's disease,Huntington's disease, Alzheimer's, ischemia, stroke, dystonia,amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) orother neurological disorders such as cerebral palsy.

In some embodiments, the delivered stimulation can be referred to astranscutaneous electrical spinal cord stimulation (tESCS) or painlesscutaneous enabling motor control (pcEmc) and are used interchangablyherein. The stimulation can be applied in the region of the T11-T12vertebrae with a frequency of 5-40 Hz and may elicit voluntary step-likemovements in healthy subjects with their legs suspended in agravity-neutral position. Amplitude of evoked step-like movements mayincrease with increasing tESCS or pcEmc frequency. Frequency of evokedstep-like movements may not depend on the frequency of tESCS or pcEmc.

In some embodiments, tESCS or pcEmc can be used as a noninvasive methodin rehabilitation of spinal pathology. By way of non-limiting examples,application of tESCS or pcEmc activates spinal networks (SNs), in partvia the dorsal roots and the gray matter of the spinal cord. Whenactivated, the SNs may (a) enable voluntary movement of muscles involvedin at least one of standing, stepping, reaching, grasping, voluntarilychanging positions of one or both legs, breathing, swallowing, chewing,coughing, speech control, voiding the patient's bladder, voiding thepatient's bowel, postural activity, and locomotor activity; (b) enableor improve autonomic control of at least one of cardiovascular function,body temperature, and metabolic processes; (c) help facilitate recoveryof at least one of an autonomic function, sexual function, vasomotorfunction, and cognitive function; and/or (d) help to resolve and/orblock pain and spasm, and improve or restore sensory function.

The paralysis may be a motor complete paralysis or a motor incompleteparalysis. The paralysis may have been caused by a spinal cord injuryclassified as motor complete or motor incomplete. The paralysis may havebeen caused by an ischemic or traumatic brain injury. The paralysis mayhave been caused by an ischemic brain injury that resulted from a strokeor acute trauma. By way of another example, the paralysis may have beencaused by a neurodegenerative brain injury. The neurodegenerative braininjury may be associated with at least one of Parkinson's disease,Huntington's disease, Alzheimer's, dystonia, ischemia, stroke,amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS),and cerebral palsy. In another embodiment, the paralysis may have beencaused or induced by a reaction to a drug, a prescribed or holisticmedication, vitamin, or mineral supplement. In one example embodiment,the paralysis may have been caused or induced by a reaction to ananesthetic drug.

In one example embodiment, a neuromodulation system may be configured toapply electrical stimulation to a portion of a spinal cord of thesubject. The electrical stimulation may be applied by at least oneelectrode that is applied to the skin surface of the subject. Such anelectrode may be positioned on at least one of a thoracic region, acervical region, a lumbosacral region, a sacral region of the spinalcord, and/or the brainstem. Electrical stimulation may be delivered at1-40 Hz at 1-200 mA. The electrical stimulation may include at least oneof tonic stimulation and intermittent stimulation. The electricalstimulation may include simultaneous or sequential stimulation ofdifferent regions of the spinal cord.

In one example embodiment, where the paralysis was caused by a spinalcord injury at a first location along the spinal cord, the electricalstimulation may be applied by an electrode that is on the spinal cord ofthe patient at a second location below the first location along thespinal cord relative to the patient's brain. In other words, the atleast one electrode can be placed below a site of spinal injury.

In one embodiment, the systems and methods described herein may includestimulation and/or recording of a second or multiple electrode(s) placedon or over a muscle, nerve, on or near a target end organ or bodilystructure. In some embodiments, this second or multiple electrode(s) maybe placed transcutaneously or can be implanted. The additionalelectrode(s) can be in communication with the first electrode through aconnection to the first electrode control module by means of either ahardwire or wireless connection. In another embodiment, the secondelectrode or multiple electrode(s) may be implanted within the subjectin various locations and to various depths on, over or near a muscle,nerve, or target end organ.

In one embodiment, methods may include administering one or more activeagents or drugs to the patient. In one embodiment, the active agent ordrug can be a neuropharmaceutical agent. The neuropharmaceuticalagent(s) may include at least one of a serotonergic drug, a dopaminergicdrug, a noradrenergic drug, a monoaminergic drug, GABAergic drug, andglycinergic drugs. By way of non-limiting examples, theneuropharmaceutical agents may include at least one of 8-OHDPAT, Way100.635, Quipazine, Ketanserin, SR 57227A, Ondanesetron, SB 269970,Buspirone, Methoxamine, Prazosin, Clonidine, Yohimbine, SKF-81297,SCH-23390, Quinpirole, and/or Eticlopride.

The neuropharmaceutical agent may be administered orally, or byintramuscular, intravenous, or intrathecal injection. In otherembodiments, the neuropharmaceutical agent may be administered rectallyor topically such as a transdermal liquid, cream, or ointment. Inembodiments, the agent can be administered via a drug pump and theadministrative pump may be in communication and under control of theelectric stimulator control module.

The electrical stimulation may be defined by a set of parameter values,and activation of the selected spinal circuit may generate aquantifiable result. In one example embodiment, the neuromodulationsystem is configured to repeat and use electrical stimulation havingdifferent sets of parameter values to obtain quantifiable resultsgenerated by each repetition. Thereafter, a machine learning method maybe executed by at least one computing device. The machine learningmethod can build a model of a relationship between the electricalstimulation applied to the spinal cord and the quantifiable resultsgenerated by activation of the at least one spinal circuit. A new set ofparameters may be selected based on the model. By way of a non-limitingexample, the machine learning method may implement a Gaussian ProcessOptimization or a “Dueling Bandit” machine learning paradigm.

In one example embodiment, the neuromodulation system can be configuredto enable at least one function selected from a group consisting ofpostural and/or locomotor activity, voluntary movement of leg position,when not bearing weight, improved ventilation, swallowing, speechcontrol, voluntary voiding of the bladder and/or bowel, return of sexualfunction, autonomic control of cardiovascular function, body temperaturecontrol, and normalized metabolic processes, in a human subject having aneurologically derived paralysis. In one embodiment, the neuromodulationsystem can be configured to enable voluntary movement or voluntarybodily functions.

Methods can include stimulating a subject's spinal cord using at leastone surface electrode and may include simultaneously subjecting thesubject to physical training that exposes the subject to relevantpostural proprioceptive signals, locomotor proprioceptive signals, andsupraspinal signals while being stimulated with tESCS or pcEmc. In otherembodiments, the methods may also include the delivery of a drug. Atleast one of the stimulation and physical training modulates, provokesor incites in real time the electrophysiological properties of spinalcircuits in the subject so the spinal circuits are activated by at leastone of supraspinal information and proprioceptive information derivedfrom the region of the subject where the selected one or more functionsare facilitated.

The region where the selected one or more functions are facilitated mayinclude one or more regions of the spinal cord that control: (a) lowerlimbs; (b) upper limbs and brainstem for controlling speech; (c) thesubject's bladder; and/or (d) the subject's bowel and/or other endorgan. The physical training may include standing, stepping, sittingdown, lying down, reaching, grasping, stabilizing sitting posture,stabilizing standing posture, practicing speech, swallowing, chewing,deep breathing, and coughing.

The surface electrode may include an array of one or more electrodesstimulated in a monopolar biphasic configuration. Such a surfaceelectrode may be placed over at least one of a lumbar, a lumbosacral orsacral portion of the spinal cord, a thoracic portion of the spinalcord, a cervical portion of the spinal cord, and/or the brainstem.

The stimulation may include continuous stimulation and/or intermittentstimulation. The stimulation may include simultaneous or sequentialstimulation of different spinal cord regions. Optionally, thestimulation pattern may be under control of the subject.

The physical training may include inducing a load bearing positionalchange in the region of the subject where locomotor activity is to befacilitated. In other embodiments, the physical training may includeinducing a load bearing positional change in the region of the subjectwhere voluntary locomotor activity is to be facilitated. The loadbearing positional change in the subject may include standing, stepping,reaching, and/or grasping. The physical training may include roboticallyguided training.

In one example embodiment, a method includes placing an electrode on thepatient's spinal cord, positioning the patient in a training deviceconfigured to assist with physical training that is configured to induceneurological signals derived from the portion of the patient's bodyhaving motor dysfunction, and applying electrical stimulation to aportion of a spinal cord of the patient.

Another exemplary embodiment is a system that includes a training deviceconfigured to assist with physically training the patient, at least onesurface electrode array configured to be applied on the patient's spinalcord, and a stimulation generator connected to the electrode. Whenundertaken, the physical training induces neurological signals derivedfrom the portion of the patient's body having the motor dysfunction. Thestimulation generator is configured to apply electrical stimulation tothe electrode. In some embodiments, the system can induce voluntarymovements as described herein.

In another embodiment, the stimulation or stimulator generator connectedto the at least one electrode is also configured to communicate with anexercise device. The stimulation or stimulator generator can also beconfigured to receive, transmit and/or store data thereby creating aclosed loop system. When undertaking physical training, the stimulatorcan auto adjust the stimulation parameters based on the interpretationof the data collected.

Additional features and advantages are described herein, and will beapparent from the following Detailed Description and figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a high level block diagram of an example network communicatingsystem, according to an example embodiment of the system disclosedherein.

FIG. 2 is a detailed block diagram showing an example of a computingdevice, according to an example embodiment of the system disclosedherein.

FIG. 3 is a block diagram of an example neuromodulation system inaccordance with one example embodiment of the system disclosed herein.

FIG. 4 is a flowchart illustrating an example procedure for delivering agenerated first signal and a generated second signal.

FIGS. 5A and 5B are diagrammatic views of an example neuromodulationsystem, illustrating an example arrangement or placement of a pluralityof electrodes.

FIG. 6 is a diagrammatic view of alternative arrangements of differenttypes of electrodes.

FIG. 7 is a diagrammatic view of an example signal which is delivered toa mammal.

FIG. 8, panels a and b, show motor responses in the muscles of the rightleg to the tESCS with a frequency of 1 Hz and an amplitude of 75-100 mA(showed at the left of the recordings). The responses in the m. rectusfemoris and m. biceps femoris (RF and BF, respectively), as well as inthe m. tibialis anterior and m. gastrocnemius (TA and MG, respectively)are shown. At the right bottom of the lower recording, there are marksof time in ms, the same for all the muscles, and marks of the amplitudein mV.

FIGS. 9A and 9B show electrical activity of the leg muscles andmovements in the leg joints evoked by tESCS with frequencies of 5 and 30Hz. FIG. 2A: Subject R: the cinematogramms of the joint movements of theright leg and the EMGs of the hip muscles of the right and left legs areshown. Under the EMG, there is a mark of the stimulus. At the right ofthe cinematogram and EMGs, there are vertical marks of the amplitude inangle degrees and mV, respectively. The duration of records is 40 s.FIG. 2B: Subject S: the EMGs of the hip and ankle muscles of the rightleg and the goniograms of the knee joints of the right and left legs;the arrows at the top show the beginning and end of stimulation; thehorizontal and vertical labels next to EMG, 10 s and 0.5 mV,respectively; the vertical mark to the right of the goniograms, 200 m V.H, hip; Kn, knee; Ank, ankle; RF, m. rectus femoris; BF, m. bicepsfemoris; T A, m. tibialis anterior; M G, m. gastrocnemius; (r), on theright; (1), on the left.

FIG. 10 EMGs (left) and trajectories of reflective markers attached tothe right leg; kinematograms (right) recorded during voluntary steppingmovements (vol) and movements caused by tESCS with frequencies of 5 and30 Hz. The duration of records is 10 s. Black and gray lines showmovements in the hip and knee joints, along with calibrations forchanges in joint angles respectively. The remaining designations are thesame as in FIG. 2.

FIG. 11, panels A-E, show interarticular coordination during voluntarystepping movements (vol) and movements caused by tESCS with frequenciesof 5 and 30 Hz. Reconstruction of the movements of the right leg duringone stepping cycle obtained by processing the cinematograms of the(Panel A) forward and (Panel B) backward movements of legs,respectively; the coordination of movements in the (Panel C) hip andknee joints, (Panel D) knee and ankle joints; and (Panel E) thetrajectory of a big toe. Subject R.

FIG. 12, panels a-f, show the average amplitude of movements in the hip(H), knee (Kn), and ankle (Ank) joints caused by tESCS with a frequencyof 5-40 Hz recorded during the first 15 s after the start ofstimulation. The ordinate shows angular degrees. (Panels a, b) SubjectS, different strategies; (Panel b) subject R; (Panel c) subject B;(Panel d) subject E; (Panel e) subject G; (Panel f) subject K. Errorbars, standard deviation. Asterisks, significant differences inamplitude recorded during tESCS with a frequency of 5 Hz, p≤0.05.

FIG. 13 illustrates an experimental timeline. The experimental plan isdivided into three segments. During the first four weeks (t₁ to t₂,Train Stim) the subjects were trained with pcEmc at T11, Co1, andT11+Co1 plus conditioning. In the second phase (t₂-t₄, Maintenance)pcEmc tests were administered weekly using less intense stimulation atT11 or Co1, no simultaneous stimulation, and no conditioning procedures.This 10-week phase of the experimental protocol was designed toestablish a stable functional baseline to more clearly differentiate theeffects of pcEmc plus fEmc from pcEmc alone. The final four-week phase(t₄-t₆, Train Stim Drug) consisted of pcEmc plus conditioning asperformed in the first phase with the addition of fEmc. S1-S5, Subjects1-5.

FIGS. 14A and 14B illustrate facilitation of stepping-like movementsduring non-invasive T11 and/or Co1 spinal cord stimulation. FIG. 14Aillustrates the position of the legs of a paralyzed subject when in thegravity-neutral apparatus. FIG. 14B illustrates mean±SEM (n=5 subjects)angular displacements of the hip and knee at the Pre-Train and Post-Drugphases. Hamstring (HM), tibialis anterior (TA), and medial gastrocnemius(MG) raw EMG and angular displacement at the knee during leg movementsin the presence of stimulation at T11, Co1, or T11+Co1 at the Pre-Train(t₁) and Post-Drug (t₆) phases is shown. Arrows indicate the time thestimulation is turned on. A “*” indicates that results are significantlydifferent from Pre-Train at P<0.05.

FIGS. 15A and 15B illustrate voluntary control of leg movements enabledby pcEmc, fEmc, and training. Vastus lateralis (VL), hamstrings (HM),tibialis anterior (TA), and soleus raw EMG and angular displacement atthe knee during leg oscillations with a voluntary effort alone (Vol),stimulation at T11, Co1, or T11+Co1 alone (Stim), and Vol+Stim at thePre-Train (FIG. 15A; t₁) and Post-Drug (FIG. 15B; t₆) phases. FIG. 15Billustrates mean±SEM (n=5 subjects) knee angular displacements at thePre-Train (t₁), Post-Train (t₂), and Post-Drug (t₆) phases under eachcondition described in (FIG. 15A) and (FIG. 15B). The dashed and dotteddashed horizontal lines indicate the mean voluntary effort at t₁ and t₂,respectively. The percentiles in t₆ reflect differences between t₆ andt₁ and t₆ and t₂, respectively. An “*” indicates a result that issignificantly different from Vol; ‡, significantly different from Stim;An “**” indicates a result that is significantly different from Vol at(t₁); ‡‡, a significantly different from Vol+Stim at (t₁). An “**”indicates a result that is significantly different from Vol at (t₂); ‡‡,significantly different from Vol+Stim at (t₂), all at P<0.05.

FIGS. 16A-16C illustrate subject specific kinematics responses andnon-linear principal component analyses. Mean angular displacements ofthe knee at the (FIG. 16A) Pre-Train, Post-Train, and Post-Drug phasesfor each subject during Vol and Vol+Stim. S1-S5, subjects 1-5. FIG. 16Billustrates a nonlinear principal component analysis (NL-PCA) to distillnon-parametric multivariate kinematics cross-correlations into principalcomponent (PC) patterns. PC loading matrix depicts the relationshipbetween variables and the extracted PC patterns. Positive loadings arered and inverse loadings are blue. Loading weights were used tocalculate PC scores. FIG. 16C illustrates three-way repeated measuresANOVA for testing the impact of Stim, Vol, and Vol+Stim on theimprovement of the kinematics based on the PC1 score. FIG. 16Cillustrates interaction of Stim by Drug modulation on the improvement ofthe kinematics based on the PC1 score: significance was assessed byfactorial 3-way within subjects ANOVA followed by post-hoc one-way ANOVAand Tukey's test. An “*” represents a value significantly different fromVol; ‡, significantly different from Stim; ‡‡, significantly differentfrom Pre-Train. ‡‡, significantly different from Post-Train, all atP<0.05.

FIGS. 17A-17C illustrate voluntary oscillatory limb activity atdifferent phases of the study. FIG. 17A illustrates an example of VL andHM EMG activity and hip and knee displacements during voluntary legoscillations without pcEmc for Subject 1 during the Pre-Train (t₁) andPost-Drug (t₅) phases. FIG. 17B illustrates mean±SEM (n=5 subjects)range of oscillations of the hip and knee at the six test recording timepoints (t₁-t₆). FIG. 17C illustrates AIS motor scores at t₁, t₂, and t₆for individual subjects (S1-S5) and the average for all subjects. An “*”represents a significant difference between t₅-t₆ vs. t₁-t₄. FL,flexion; EX, extension; DF, dorsiflexion; PF, plantarflexion.

FIGS. 18A-18D illustrate modulation of evoked potentials with andwithout voluntary effort. FIG. 18A illustrates raw EMG from the TA andMG muscles under the influence of stimulation at T11, Co1, and T11+Co1with and without voluntary effort to oscillate the legs(flexion-extension-flexion) when placed in a gravity-neutral position.FIG. 18B illustrates evoked potentials generated within the shaded areasin FIG. 18A without and with voluntary effort. The sequence of traces istriggered from the stimulation pulse with the lowest trace being thefirst and the top trace being the last response. FIG. 18C illustrates anoverlay of multiple responses (T11, 0-33 ms and Co1, 0-200 ms) duringflexion and extension without and with voluntary effort. FIG. 18Dillustrates a schematic summary of the variations in 20-35 ms TA(Flexor-F) and MG (Extensor-E) responses (see FIG. 18B) reflects howspinally evoked potentials can be gated with voluntary input. The dottedlines reflect minimal or no evoked potential and the thin and thicksolid lines indicate modest and high amplitude evoked potentials.Generally Co1 stimulation evoked more consistent responses in bothmuscles than T11 or T11+Co1 stimulation.

FIGS. 19A-19D illustrate effects of proprioceptive conditioning onvoluntary leg movements. FIG. 19A illustrates an example of raw EMG andhip and knee angular displacements from the first and last 30 sec ofconditioning without and with stimulation at T11. FIG. 19B illustratesscatter plots between filtered EMG activity of antagonistic muscle pairs(VL vs. HM, TA vs. Soleus and TA vs. MG) for the first 5 sec from eachsegment illustrated in FIG. 19A. FIG. 19C illustrates when NL-PCA wasused to distill non-parametric multivariate kinematicscross-correlations into PC patterns. PC loading matrix depicts therelationship between variables and the extracted PC patterns. FIG. 19Dillustrates three-way repeated measures ANOVA of the impact of Vol,Stim, and Vol+Stim using PC1 outcome as the endpoint. FIG. 19Dillustrates the interaction of Stim by Conditioning modulation. ‡,significantly different from Stim; ‡‡, significantly different Pre-Cond,all at P<0.05.

FIG. 20 illustrates MRI images of the five SCI subjects. Sagittal MRIshowing the approximate location (spinal cord segment) of the cervicalor thoracic spinal cord injury in each subject: S1—injury level T3-T4,S2—injury level C5-C6, S3—injury level C6, S4—injury level C7, andS5—injury level T3-T4. Normal tissue at the injury site is replaced by ahigh or mixed intensity signal representing a glial scar. Spinal cordtissue distal and proximal to the injury site appears intact without anyevidence of progressive post-traumatic syrinx formation or ongoingcompressive lesion. Some image artifact from the instrumentationdistorting the spinal cord image can be visualized.

FIGS. 21A-21F illustrate an electrophysiological assessment of injuryseverity. EMG from the TA, MG and soleus was recorded with and without amaximum voluntary effort to dorsiflex or plantarflex with pcEmc at T11.The histograms indicate peak-to-peak amplitudes of the evoked potentialsin the absence of voluntary effort (dark) and in the presence ofvoluntary effort (light). FIG. 21A illustrates results from an uninjuredsubject. FIGS. 21B-21F illustrate SCI subjects identification inparentheses. MP, manual pulse to generate the dorsiflexion orplantarflexion effort. Electrophysiological assessment of injuryseverity. EMG from the TA, MG and soleus was recorded with and without amaximum voluntary effort to dorsiflex or plantarflex with pcEmc at T11.The histograms indicate peak-to-peak amplitudes of the evoked potentialsin the absence of voluntary effort (dark) and in the presence ofvoluntary effort (light). MP is manual pulse to generate thedorsiflexion or plantarflexion effort.

DETAILED DESCRIPTION

The present disclosure relates in general to the field of neurologicaltreatment and rehabilitation for injury and disease including traumaticspinal cord injury, non-traumatic spinal cord injury, stroke, movementdisorders, brain injury, and other diseases or injuries that result inparalysis and/or nervous system disorder. Systems and devices areprovided to facilitate recovery of posture, locomotion, and voluntarymovements such as those of the arms, trunk, and legs, and recovery ofautonomic, sexual, vasomotor, speech, swallowing, chewing, respiratoryand cognitive function, in a human subject having spinal cord injury,brain injury, or any other neurological disorder.

Described herein generally are stimulation strategies and methods ofpcEmc or tESCS and optionally a pharmacological enabling motor control(fEmc) strategy to neuromodulate the physiological state of the spinalcord in individuals with paralysis, for example, motor completeparalysis. The strategies can assist in regaining some voluntarylocomotor-like leg movements after motor complete paralysis or othervoluntary movements of body parts affected by spinal cord injury.

Systems for delivering stimulation are also described. The systems canelectrically activate the spinal circuitry via electrodes placed on theskin overlying the spinal cord such as the lower thoracic andlumbosacral vertebrae.

The systems and methods can also include the administration of at leastone drug. In some embodiments, the drug is a monoaminergic drug. In someembodiments, the monoaminergic drug can be administered in combinationwith stimulation (e.g., pcEmc+fEmc) to provide voluntarily movement,such as but not limited to step-like movements of the lower limbs. Insome embodiments, the monoaminergic drug can be buspirone.

Further, the results provided herein demonstrate the presently describedsystems and methods' ability to bring about voluntary movement in apatient with motor complete paralysis. However, in some embodiments,there herein described systems and methods can bring about voluntarymovement in a patient with motor incomplete paralysis.

These systems and methods can transform brain-spinal neuronal networksfrom a dormant to a functional state sufficiently to enable recovery ofvoluntary movement. In some embodiments, the systems and methodsfacilitate voluntary control of locomotor-like stepping with pcEmc ortESCS and optionally fEmc.

For example, in some embodiments, a single treatment session with pcEmcor tESCS and fEmc three minutes of passive movements can furtherfacilitate voluntary outputs. Also, in some embodiments, spinally evokedmotor potentials can be readily modulated voluntarily, providingfunctional and electrophysiological evidence of the re-establishment ofconnectivity among neural networks between the brain and the spinalcord.

The devices and methods described herein can re-engage descending inputthat projects to spinal locomotor networks after partial or completemotor paralysis. The present systems and methods can use pcEmc or tESCSand optionally fEmc. In some embodiments, pcEmc or tESCS and optionallyfEmc are combined with training. When used with training, a re-engagingof descending input that projects to spinal locomotor networks canresult. Thus, in some embodiments, inducement of voluntary movement ofbody parts can result.

The systems and methods can enable movement to occur voluntarily ratherthan being induced directly by stimulation. For example, pcEmc or tESCSoptionally coupled with fEmc can enable the re-engagement of aprogressively increasing complex neural network, providing the substratefor previously dormant circuitry to regain function. Although in someembodiments, some dysfunctional reorganization of the networks can occurafter a spinal cord injury thereby limiting the recovery of coordinatedmovements, re-engagement may not be prevented. The quality of therecovered coordination reflects some aberrant and/or limitedconnectivity of the newly emerged descending control of the spinalnetworks.

In some embodiments, when combining pcEmc or tESCS and optionally fEmcwith training, both animal and human results can show more normal levelsof coordination and/or recruitment of motor pools. In some embodiments,the training can be extensive training. In some embodiments, more normallevels of coordination and/or recruitment of motor pools can be realizedat least during movements such as stepping can be recovered.

In some embodiments, functional brain-to-spinal cord connectivity incompletely paralyzed individuals can be facilitated with electricaland/or pharmacological neuromodulation when presented concomitantly withtraining of neural networks that control stepping-like movements.

In some embodiments, when combining pcEmc or tESCS and/or fEmc withtraining, the systems and methods can provide improvements in functionalmeasures of spinal cord injury converting subjects from motor complete(AIS B) to motor incomplete (AIS C), such as within a relatively shortperiod of time. For example, as described herein, in 5/5 individualsassumed to be completely paralyzed, two noninvasive interventions canfacilitate recovery of voluntarily controlled sensorimotor function.Also, given anatomical and physiological incompleteness of spinal cordinjuries typically diagnosed otherwise as “completely paralyzed” placessome sense of urgency in resolving the uncertainty of the diagnosis andtreatment strategies that should be followed after paralysis.

The present systems and methods can improve postural, locomotor, andother functions that are directly defined by the individual's mobility.For example improvements can be attained in autonomic function ofmultiple physiological systems, such as improved cardiovascular andbladder control, sexual function, and temperature regulation.

The systems described herein may be readily realized in a networkcommunications system. A high level block diagram of an example networkcommunications system 100 (“system 100”) is illustrated in FIG. 1. Inthis example, system 100 includes neuromodulation system 102 andinformation processing system 104.

Information processing system 104 may include a variety of devices, suchas desktop computers which typically include a user display forproviding information to users and various interface elements as will bediscussed in further detail below. Information processing system 104 mayinclude a cellular phone, a personal digital assistant, a laptopcomputer, a tablet computer, or a smart phone. In some exampleembodiments, information processing system 104 may include any mobiledigital device such as a smartphone, cellular phone, tablet, laptopcomputer, ultrabook computer, pager, or the like. Further, informationprocessing system 104 may include smart phones based on variouscommercially available operating systems. In these embodiments,information processing system 104 is preferably configured to download,install and execute various application programs.

Information processing system 104 may communicate with neuromodulationsystem 102 via a connection to one or more communications channels 106such as the Internet or some other data network, including, but notlimited to, any suitable wide area network or local area network. Itshould be appreciated that any of the devices and systems describedherein may be directly connected to each other instead of over anetwork. At least one server 108 may be part of network communicationssystem 100, and may communicate with neuromodulation system 102 andinformation processing system 104.

Information processing system 104 may interact with a large number ofusers at a plurality of different neuromodulation systems 102.Accordingly, information processing system 104 may be a high endcomputer with a large storage capacity, one or more fastmicroprocessors, and one or more high speed network connections.Conversely, relative to an example high end information processingsystem 104, each neuromodulation system 102 may include less storagecapacity, a single microprocessor, and a single network connection.

It should be appreciated that users as described herein may include anyperson or entity which uses the presently disclosed system and mayinclude a wide variety of parties. For example, the users describedherein may refer to various different entities, including patients,physicians, administrative users, mobile device users, privateindividuals, and/or commercial partners. It should also be appreciatedthat although the user in this specification is often described as apatient, the patient may be instead any of the users described herein.

Neuromodulation system 102 and/or servers 108 may store files, programs,databases, and/or web pages in memories for use by informationprocessing system 104, and/or other information processing systems 104or servers 108.

Neuromodulation system 102 and/or server 108 may be configured accordingto its particular operating system, applications, memory, hardware,etc., and may provide various options for managing the execution of theprograms and applications, as well as various administrative tasks.Information processing system 104 and/or server 108 may interact via atleast one network with at least one other information processing system104 and/or server 108, which may be operated independently. Informationprocessing systems 104 and servers 108 operated by separate and distinctentities may interact together according to some agreed upon protocol.

A detailed block diagram of the electrical systems of an examplecomputing device is illustrated in FIG. 2. The example computing devicemay include any of the devices and systems described herein, includingneuromodulation system 102, information processing system 104 and server108. In this example, the example computing devices may include mainunit 202 which preferably includes at least one processor 204electrically connected by address/data bus 206 to at least one memorydevice 208, other computer circuitry 210, and at least one interfacecircuit 212. Processor 204 may be any suitable processor. Processor 204may include one or more microprocessors, central processing units(CPUs), computing devices, microcontrollers, digital signal processors,or like devices or any combination thereof. Memory 208 preferablyincludes volatile memory and non-volatile memory. Preferably, memory 208stores software program(s) that interact with the other devices insystem 100 as described below. This program may be executed by processor204 in any suitable manner. In an example embodiment, memory 208 may bepart of a “cloud” such that cloud computing may be utilized byneuromodulation system 102, information processing system 104 and server108. Memory 208 may also store digital data indicative of documents,files, programs, web pages, etc. retrieved from computing devices 102,103 and 104 and/or loaded via input device 214.

Interface circuit 212 may be implemented using any suitable interfacestandard, such as an Ethernet interface and/or a Universal Serial Bus(USB) interface. At least one input device 214 may be connected tointerface circuit 212 for entering data and commands into main unit 202.For example, input device 214 may be at least one of a keyboard, mouse,touch screen, track pad, track ball, isopoint, image sensor, characterrecognition, barcode scanner, and a voice recognition system.

As illustrated in FIG. 2, at least one display device 112, printers,speakers, and/or other output devices 216 may also be connected to mainunit 202 via interface circuit 212. Display device 112 may be a cathoderay tube (CRTs), a liquid crystal display (LCD), or any other suitabletype of display device. Display device 112 may be configured to generatevisual displays during operation of neuromodulation system 102,information processing system 102 and/or server 108. A user interfacemay include prompts for human input from user 114 including links,buttons, tabs, checkboxes, thumbnails, text fields, drop down boxes,etc., and may provide various outputs in response to the user inputs,such as text, still images, videos, audio, and animations.

At least one storage device 218 may also be connected to main device orunit 202 via interface circuit 212. At least one storage device 218 mayinclude at least one of a hard drive, CD drive, DVD drive, and otherstorage devices. At least one storage device 218 may store any type ofdata, such content data, statistical data, historical data, databases,programs, files, libraries, pricing data and/or other data, etc., whichmay be used by neuromodulation system 102, information processing system104 and/or server 108.

Neuromodulation system 102, information processing system 104 and/orserver 108 may also exchange data with other network devices 220 via aconnection to network 106. Network devices 220 may include at least oneserver 226, which may be used to store certain types of data, andparticularly large volumes of data which may be stored in at least onedata repository 222. Server 226 may include any kind of data 224including user data, application program data, content data, statisticaldata, historical data, databases, programs, files, libraries, pricingdata and/or other data, etc. Server 226 may store and operate variousapplications relating to receiving, transmitting, processing, andstoring the large volumes of data. It should be appreciated that variousconfigurations of at least one server 226 may be used to support andmaintain system 100. In some example embodiments, server 226 is operatedby various different entities, including private individuals,administrative users and/or commercial partners. Also, certain data maybe stored in neuromodulation system 102, information processing system104 and/or server 108 which is also stored on server 226, eithertemporarily or permanently, for example in memory 208 or storage device218. The network connection may be any type of network connection, suchas an Ethernet connection, digital subscriber line (DSL), telephoneline, coaxial cable, wireless connection, etc.

Access to neuromodulation system 102, information processing system 104and/or server 108 can be controlled by appropriate security software orsecurity measures. A user's access can be defined by neuromodulationsystem 102, information processing system 104 and/or server 108 and belimited to certain data and/or actions. Accordingly, users of system 100may be required to register with neuromodulation system 102, informationprocessing system 104 and/or server 108.

As noted previously, various options for managing data located withinneuromodulation system 102, information processing system 104 and/orserver 108 and/or in server 226 may be implemented. A management systemmay manage security of data and accomplish various tasks such asfacilitating a data backup process. The management system may update,store, and back up data locally and/or remotely. A management system mayremotely store data using any suitable method of data transmission, suchas via the Internet and/or other networks 106.

FIG. 3 is a block diagram showing an example neuromodulation system 300.It should be appreciated that neuromodulation system 300 illustrated inFIG. 3 may be implemented as neuromodulation system 102.

As illustrated in FIG. 3, in this example, neuromodulation system 300may include neuromodulation stimulator device 302 which is operativelyconnected to at least one electrode 308. Neuromodulation stimulatordevice 302 may be connected to at least one electrode 308 in anysuitable way. In one example, neuromodulation stimulator device 302 isdirectly connected to at least one electrode 308. In another example,where at least one electrode 308 is implanted, neuromodulationstimulator device 302 is connected to at least one electrode 308 via awireless connection.

Referring to FIG. 3, in this example, neuromodulation stimulator device302 includes first signal generator 304, second signal generator 306 anddatabase system 310. First signal generator 304, second signal generator306 and database system 310 may include software and/or hardwarecomponents, such as a field programmable gate array (FPGA) or anapplication specific integrated circuit (ASIC), which performs certaintasks. First signal generator 304, second signal generator 306 anddatabase system 310 may advantageously be configured to reside on anaddressable storage medium and configured to be executed on one or moreprocessors. Thus, first signal generator 304, second signal generator306 and database system 310 may include, by way of example, components,such as software components, object-oriented software components, classcomponents and task components, processes, functions, attributes,procedures, subroutines, segments of program code, drivers, firmware,microcode, circuitry, data, databases, data structures, tables, arrays,and variables. The functionality provided for in the components andmodules may be combined into fewer components and modules or furtherseparated into additional components and modules.

Database system 310 may include a wide variety of data. For example,database system may include any of the following data: user data,application program data, content data, statistical data, historicaldata, databases, programs, files, libraries, pricing data and/or otherdata, etc.

In some example embodiments, at least one electrode 308 includes singleor multiple arrays and may be placed on the skin overlying the spinalcord, spinal nerve(s), nerve root(s), ganglia, peripheral nerve(s),brain stem or target areas such as skeletal muscles.

In some embodiments, the at least one electrode is made of a conductinggel or reservoir of water soluble/salt solution. In some embodiments,the implantable electrodes are made of biocompatible material such assilicone and may be embedded with an inert metal such as gold orplatinum wires.

As illustrated in FIG. 4, a flowchart of an example process 400 includesdelivering a generated first signal and a generated second oroverlapping signal. Process 400 may be embodied in one or more softwareprograms which are stored in one or more memories and executed by one ormore processors. Although process 400 is described with reference to theflowchart illustrated in FIG. 4, it should be appreciated that manyother methods of performing the acts associated with process 400 may beused. For example, the order of many of the steps may be changed, someof the steps described may be optional, and additional steps may beincluded.

More specifically, in one example, the neuromodulation system generatesa first signal, as indicated by block 402. For example, first signalgenerator 302 may generate a 40 Hz biphasic signal.

As indicated by block 404, the neuromodulation system generates a secondsignal. For example, second signal generator 304 may generate anoverlapping 10 kHz signal.

As indicated by block 406, the neuromodulation system delivers thegenerated first signal and the generated second signal. For example, theneuromodulation system may transcutaneously deliver, via an electrodepositioned on a spinal cord, the generated 40 Hz biphasic signal withthe overlapping 10 kHz signal.

FIGS. 5A and 5B are diagrammatic views of an example neuromodulationsystem 500, illustrating an example arrangement or placement of aplurality of electrodes. In this example embodiment, neuromodulationsystem 500 includes trancutaneous electrical stimulator 502 which isoperatively connected to at least one electrode or active electrode 504,first ground electrode 506 and second ground electrode 508. As bestshown in FIG. 5B, in this example arrangement, active electrode 504 isdisposed on the user's trunk. Such a configuration enables theneuromodulation system to deliver symmetrical activation.

FIG. 6 is a diagrammatic view of alternative arrangements of differenttypes of electrodes.

An active electrode may be placed in any suitable location. For example,as shown in FIG. 6, an active electrode may be placed overlying theuser's neck, as shown by 602 a, overlying the user's trunk, as shown by602 b, overlying the user's lower back, as shown by 602 c, and/oroverlying the base of a skull (i.e., the brainstem) (not shown).

As illustrated in FIG. 6, superficial electrodes may be positioned in aplurality of different locations. For example, superficial electrodes604 a are positioned overlying muscles of the neck or throat.Superficial electrodes 604 b may be positioned overlying muscles of thediaphragm. Superficial electrodes 604 c may be positioned overlying thekidney region. Superficial electrodes 604 d may be positioned overlyingthe stomach region. Superficial electrode 604 e may be positionedoverlying the pubic region. Superficial electrodes 604 f may bepositioned overlying the shoulder or upper arm. Superficial electrodes604 g may be positioned overlying the biceps or upper arm. Superficialelectrodes 604 h may be positioned overlying the forearm. Superficialelectrodes 604 i may be positioned overlying the upper leg or thigh.Superficial electrodes 604 j may be positioned overlying the lower legor calf. Superficial electrodes 604 k may be positioned overlying thelower leg or shin. Superficial electrodes 604 a may be positionedoverlying muscles of the neck or throat.

In one example embodiment, at least one electrode is configured to beimplanted in a user. In this example, system 100 includes an electricalstimulator which wirelessly communicates with the at least one implantedelectrode. In one example embodiment, the transcutaneous electricalstimulator causes the implanted electrode to deliver the generated firstsignal and the generated second signal. In some embodiments, the atleast one implanted electrode is configured to record data andwirelessly transmit the recorded data to the electrical stimulator. Insome embodiments, where the at least one electrode is implanted, the atleast one electrode is configured to deliver the first generated signaland not the second generated signal. That is, in this example, thesecond generated signal is not needed.

In some embodiments, system 100 is configured to wirelessly communicatewith adjunctive or ancillary equipment such as the footwear described inU.S. Pat. No. 7,726,206 which is hereby incorporated by reference in itsentirety. The adjunctive or ancillary equipment may include at least oneof a drug pump, drug delivery systems, physical therapy or skeletalsupport systems.

As discussed above, in some embodiments, the neuromodulation systemgenerates and delivers a first signal and a second signal. FIG. 7illustrates one example of a signal which is delivered by the modulationsystem via at least one electrode. In this example, the signal is a 1-40Hz bipolar rectangular stimulus with a duration between 0.3 and 1.0 ms,filled with a carrier frequency of 5-10 kHz. The signal illustrated inFIG. 7 may result in less skin impedance, and more comfortable andrelatively painless treatment which yields greater compliance and betteroutcomes.

In one example embodiment, the neuromodulation system includes atransistor (e.g., a push-pull transistor) which is configured to set thevoltage of the delivered signal. The signal may be coupled through atransformer to patient channels or electrodes. Using switches, thechannels or electrodes are activated and the signal is applied. Theneuromodulation system may include an opto-coupler current detectioncircuit. The signal may vary in duration, pulse frequency, pulse trainduration and number of pulse trains.

In one example embodiment, for locomotion, the delivered signal is 30-40Hz at 85-100 mA with an overlapping filling frequency of 10 kHZ.

The generated second or overlapping signal may have a frequency between5 kHz and 10 kHz. In some embodiments, the generated second signal isadjustable between 5 kHz and 10 kHz.

In one example embodiment, the neuromodulation system is configured todeliver a bipolar rectangular stimulus with a pulse duration of 0.5 ms,filled with a carrier frequency of 10 kHz.

In one example embodiment, the neuromodulation system is configured todeliver biphasic stimuli filled with a carrier frequency of 10 kHz. Inthis example, the biphasic stimuli filled with a carrier frequency of 10kHz may suppress the sensitivity of pain receptors of the subject. Inanother example embodiment, the neuromodulation system is configured todeliver biphasic stimuli filled with a carrier frequency of 5-10 kHz.

In some embodiments, the neuromodulation system sums the first generatedsignal and the second generated signal to generate a signal that isdelivered to the electrode. In some embodiments, the neuromodulationsystem includes a frequency mixer configured to add or sum the firstgenerated signal and the second generated signal.

In some embodiments, the neuromodulation system is configured to senddifferent frequencies to two or more different electrodes which may bespatially separated on the surface of a patients body.

In some embodiments, the neuromodulation system synchronizes the phasingbetween the first generated signal and the second generated signal atone point in time. In some embodiments, where the higher frequency is aninteger multiple of the lower frequency, the neuromodulation systemrepeatedly synchronizes the phasing between the first generated signaland the second generated signal.

In one example embodiment, electrical stimulation is delivered at 1-100Hz and at 30-200 mA.

In one example embodiment, electrical stimulation is delivered at 5-40Hz and at one of 0-300 mA, 1-120 mA, 20-100 mA and 85-100 mA.

In one example embodiment, the frequency of the delivered signal isadjustable. In some embodiments, the frequency of the first generatedsignal is adjustable from 0.0-40 Hz.

In some embodiments, the pulse duration of the delivered signal isadjustable. In some embodiments, the pulse duration of at least one ofthe generated signals is adjustable from 0.5-3.0 ms.

In some embodiments, the amount of amplitude of the delivered signal isadjustable. In some embodiments, the amplitude is adjustable from 0-300mA.

In some embodiments, the stimulation is continuous. In some embodiments,the stimulation is intermittent.

In some embodiments, the system enables ongoing identification of theoptimal stimulation pattern, and allows for adjustment of thestimulating pattern by: (a) auto regulation; (b) direct manual control;or (c) indirect control though wireless technology.

In some embodiments, the neuromodulation system is configured to adjuststimulation and control parameters of the stimulator to levels that aresafe and efficacious using parameters chosen to target specific neuralcomponents, or end organs and customized to each patient based onresponse to evaluation and testing.

In some embodiments, the system targets specific components of thenervous system with a desired predetermined stimulation parameter orseries of stimulation parameters. In one example, in the case oflocomotion, a monopolar electrode is placed over the paravertebralspaces of the thoracic vertebrae of T11-T12, with a reference electrodeplaced over the abdomen; the system is programmed to deliver 5-40 Hzsignal at 85-100 mA with an overlapping high frequency pulse of 10 kHz.

In some embodiments, the neuromodulation system includes at least onesensor. In one example embodiment, the neuromodulation system determinesstimulation parameters based on physiological data collected by the atleast one sensor.

The at least one sensor may include at least one of an electromyography(“EMG”) sensor, a joint angle (or flex) sensor, an accelerometer, agyroscope sensor, a flow sensor, a pressure sensor, a load sensor, asurface EMG electrode, a foot force plate sensor, an in-shoe sensor, anaccelerator, a motion capture system, and a gyroscope sensor attached toor positioned adjacent the body of the subject.

The stimulation parameters may identify a waveform shape, amplitude,frequency, and relative phasing of one or more electrical pulsesdelivered to one or more pairs of the plurality of electrodes.

The at least one sensor may be connected to the neuromodulation systemin any suitable way. For example, the at least one sensor may beconnected via wires or wirelessly.

In some embodiments, the neuromodulation system includes at least onerecording electrode. The neuromodulation system may be configured toreceive and record electrical signals received from the at least onerecording electrode. The at least one recording electrode may bepositioned on an electrode array. The electrode array may be considereda first electrode array, and the system may include a second electrodearray. The at least one recording electrode may be positioned on atleast one of the first electrode array and the second electrode array.In some embodiments, the neuromodulation system includes a recordingsubsystem which is configured to record signals from the at least onerecording electrode. The recording subsystem may include amplifierswhich may be implemented as low noise amplifiers with programmable gain.

In some embodiments, the neuromodulation system includes a plurality ofmuscle electrodes which cause muscle to move (e.g., contract) to augmentthe improved neurological function provided by the complex stimulationpatterns alone. The neuromodulation system may deliver electricalstimulation to the plurality of muscle electrodes.

In some embodiments, the neuromodulation system includes a stimulatordevice operatively connected to the electrodes. The stimulator devicemay include a casing which is configured to house a signal generator anda control module. The signal generator may be configured to signalgenerate the signals discussed herein. The control module may beconfigured to control the signal generator. The casing may be made ofmolded plastic and may be made compact and portable for single patientuse.

The neuromodulation system may be configured to determine a set ofstimulation parameters by performing a machine learning method based onsignals received from a sensor. In one example, the machine learningmethod implements a Gaussian Process Optimization or a Dueling Banditmachine learning algorithm or process.

In one example embodiment, the neuromodulation system includes aplurality of electrodes. In this example, the neuromodulation systemdelivers stimulation or generated signals via a selected one or more ofthe electrodes.

In some embodiments, the neuromodulation system may be configured withat least one of the following properties or features: (a) a form factorenabling the neurostimulator device to be worn; (b) a power generatorwith rechargeable battery; (c) a secondary back up battery; (d)electronic and/or mechanical components encapsulated in a package madefrom one or more synthetic polymer materials; (d) programmable andautoregulatory; (e) ability to record field potentials; (f) ability tooperate independently, or in a coordinated manner with other implantedor external devices; and (g) ability to send, store, and receive datavia wireless technology.

In some embodiments, the system is capable of open and closed loopfunctionality, with the ability to generate and record field potentials,evoked potentials and/or modulate membrane potentials of cells andneuronal circuits.

In some embodiments, the stimulator device includes a rechargeablebattery or AC current. In some embodiments, the stimulator deviceincludes a dual power source (e.g., back up battery). In someembodiments, the system includes a power generator with a rechargeablebattery.

In some embodiments, the non-invasive neurostimulator or neuromodulationdevices may be used to deliver therapy to patients to treat a variety ofsymptoms or conditions such as post traumatic pain, chronic pain,neuropathy, neuralgia, epilepsy, spasm, and tremor associated with andwithout Parkinson's disease.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs.

The term “motor complete” when used with respect to a spinal cord injuryindicates that there is no motor function below the lesion, (e.g., nomovement can be voluntarily induced in muscles innervated by spinalsegments below the spinal lesion.

The term “monopolar stimulation” refers to stimulation between a localelectrode and a common distant return electrode.

The term “autonomic function” refers to functions controlled by thenervous system that are controlled largely below the level ofconsciousness, and typically involve visceral functions. Illustrativeautonomic functions include, but are not limited to control of bowel,bladder, and body temperature.

The term “sexual function” refers to the ability to sustain a penileerection, have an orgasm (male or female), generate viable sperm, and/orundergo an observable physiological change associated with sexualarousal.

The term “cognitive function” refers to awareness of ones surroundingenvironment and the ability to function effectively, behaviorally, andmentally in a given environment.

In some embodiments, transcutaneous electrical stimulation (tESCS) ofthe spinal cord can induce activation locomotor circuitry in a mammal(e.g., in a human or a non-human mammal). Further, tECS of the spinalcord can induce activation voluntary locomotor circuitry in a mammal(e.g., in a human or a non-human mammal).

Also, continuous tESCS at 5-40 Hz applied paraspinally over T11-T12vertebrae at 40-70 mA can induce involuntary locomotor like steppingmovements in subjects with their legs in a gravity-independent position.In other embodiments, continuous tESCS at 5-40 Hz applied paraspinallyover T11-TI2 vertebrae at 40-70 mA can induce voluntary locomotor likestepping movements in subjects with their legs in a gravity-independentposition. An increase of frequency of tESCS from 5 to 30 Hz results inaugmentation of the amplitude of evoked stepping movements. In chronicspinal cats (3 weeks after spinal cord transection at Th8) tESCS at L5(a frequency of 5 Hz and intensity ranged from 3 to 10 mA) evoked EMGstepping pattern in hindlimb muscles in all (N=4) of tested animals,while locomotor-like movements produced by tESCS were notweight-bearing.

By non-limiting example, transcutaneous electrical stimulation can beapplied to facilitate restoration of voluntary movement, locomotion, andother neurologic function in subjects suffering with spinal cord injury,as well as other neurological injury and illness. Successful applicationcan provide a device for widespread use in rehabilitation of neurologicinjury and disease.

The neuromodulation system may facilitate or induce voluntary movementin a mammalian subject (e.g., a human) having a spinal cord injury,brain injury, or other neurological disease or injury. In certainembodiments, the neuromodulation system is configured to stimulate thespinal cord of the subject using a surface electrode where thestimulation modulates the electrophysiological properties of selectedspinal circuits in the subject so they can be activated byproprioceptive derived information and/or input from supraspinal. Insome embodiments, stimulation may be accompanied by physical training(e.g., movement) of the region where the sensory-motor circuits of thespinal cord are located. In other embodiments, the stimulation includesa biphasic signal and an overlapping high frequency pulse.

In some embodiments, the neuromodulation system is configured tostimulate the spinal cord with electrodes that modulate theproprioceptive and supraspinal information which controls the lowerlimbs during standing and/or stepping and/or the upper limbs duringreaching and/or grasping conditions. In some embodiments, proprioceptiveand cutaneous sensory information can guide the activation of themuscles in a coordinated manner and in a manner that accommodates theexternal conditions, e.g., the amount of loading, speed, and directionof stepping or whether the load is equally dispersed on the two lowerlimbs, indicating a standing event, alternating loading indicatingstepping, or sensing postural adjustments signifying the intent to reachand grasp.

Unlike approaches that involve specific stimulation of motor neurons todirectly induce a movement, the neuromodulation system described hereinenables spinal circuitry to control the movements. More specifically,the neuromodulation system described herein can exploit the spinalcircuitry and its ability to interpret proprioceptive information and torespond to that proprioceptive information in a functional way. In someembodiments, this is in contrast to other approaches where the actualmovement is induced/controlled by direct stimulation (e.g., ofparticular motor neurons).

In one example embodiment, a subject is fitted with one or more surfaceelectrodes that afford selective stimulation and control capability toselect sites, mode(s), and intensity of stimulation via electrodesplaced superficially over, for example, the lumbosacral spinal cordand/or cervical spinal cord to facilitate movement of the arms and/orlegs of individuals with a severely debilitating neuromotor disorder.The subject is provided the generator control unit and is fitted with anelectrode(s) and then tested to identify the most effective subjectspecific stimulation paradigms for facilitation of movement (e.g.,stepping and standing and/or arm and/or hand movement). Using thesestimulation paradigms, the subject practices standing and stepping,reaching or grabbing, and/or breathing and speech therapy in aninteractive rehabilitation program while being subject to spinalstimulation as described herein including a biphasic signal and anoverlapping high frequency pulse.

Depending on the site/type of injury and the locomotor activity it isdesired to facilitate, particular spinal stimulation protocols include,but are not limited to, specific stimulation sites along thelumbosacral, thoracic, and/or cervical spinal cord; specificcombinations of stimulation sites along the lumbosacral, thoracic,and/or cervical spinal cord and/or brainstem; specific stimulationamplitudes; specific stimulation polarities (e.g., monopolar and bipolarstimulation modalities); specific stimulation frequencies; and/orspecific stimulation pulse widths.

In some embodiments, the neuromodulation system is designed so that thepatient can use and control it in the home environment.

In some embodiments, the approach is not to electrically induce awalking pattern or standing pattern of activation, but toenable/facilitate it so that when the subject manipulates their bodyposition, the spinal cord can receive proprioceptive information fromthe legs (or arms) that can be readily recognized by the spinalcircuitry. Then, the spinal cord knows whether to step or to stand or todo nothing. In other words, this enables the subject to begin steppingor to stand or to reach and grasp when they choose after the stimulationpattern has been initiated.

Moreover, the neuromodulation system described herein is effective in aspinal cord injured subject that is clinically classified as motorcomplete; that is, there is no motor function below the lesion. In someembodiments, the specific combination of electrode(s)activated/stimulated and/or the desired stimulation of any one or moreelectrodes and/or the stimulation amplitude (strength) can be varied inreal time, e.g., by the subject. Closed loop control can be embedded inthe process by engaging the spinal circuitry as a source of feedback andfeed-forward processing of proprioceptive input and by voluntarilyimposing fine tuning modulation in stimulation parameters based onvisual, and/or kinetic, and/or kinematic input from selected bodysegments.

In some embodiments, the neuromodulation system is designed so that asubject with no voluntary movement capacity can execute effectivevoluntary movements such as, but not limited to standing and/or steppingand/or reaching and/or grasping. In addition, the approach describedherein can play an important role in facilitating recovery ofindividuals with severe although not complete injuries.

In some embodiments, the neuromodulation system may provide some basicpostural, locomotor and reaching and grasping patterns to a user. Insome embodiments, the neuromodulation system may provide a buildingblock for future recovery strategies. In some embodiments, a strategy ofcombining effective transcutaneous stimulation of the appropriate spinalcircuits with physical rehabilitation and pharmacological interventioncan provide practical therapies for complete SCI human patients. Such anapproach may be enough to enable weight bearing standing, steppingand/or reaching or grasping or other movements. Such capability can giveSCI patients with complete paralysis or other neuromotor dysfunctionsthe ability to participate in exercise, which is known to be highlybeneficial for their physical and mental health. In some embodiments,the neuromodulation system may enable movement with the aid of assistivewalkers. While far from complete recovery of all movements, even simplestanding and short duration walking would increase these patients'autonomy and quality of life. The neuromodulation system describedherein (e.g., transcutaneous electrical stimulation) can provide for adirect brain-to-spinal cord interface that could enable more lengthy andfiner control of movements.

While the neuromodulation systems described herein are discussed withreference to complete spinal injury, it will be recognized that they canapply to subjects with partial spinal injury, subjects with braininjuries (e.g., ischemia, traumatic brain injury, stroke, and the like),and/or subjects with neurodegenerative diseases (e.g., Parkinson'sdisease, Alzheimer's disease, Huntington's disease, dystonia,amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS),cerebral palsy, and the like).

In some embodiments, the neuromodulation system may be used inconjunction with physical training (e.g., rigorously monitored (robotic)physical training) and optionally in combination with pharmacologicaltechniques or other drug delivery. The neuromodulation system enablesthe spinal cord circuitry to utilize sensory input as well as newlyestablished functional connections from the brain to circuits below thespinal lesion as a source of control signals. The approach is thusdesigned to enable and facilitate the natural sensory input as well assupraspinal connections to the spinal cord in order to controlmovements, rather than induce the spinal cord to directly induce themovement. That is, the neuromodulation system facilitates and enhancesthe intrinsic neural control mechanisms of the spinal cord that existpost-SCI, rather than replace or ignore them.

Processing of Sensory Input by the Lumbosacral Spinal Cord: UsingAfferents as Source of Control

In some embodiments, the neuromodulation exploits spinal control oflocomotor activity. For example, the human spinal cord may receivesensory input associated with a movement such as stepping, and thissensory information can be used to modulate the motor output toaccommodate the appropriate speed of stepping and level of load that isimposed on lower limbs. Moreover, the human lumbosacral spinal cord hascentral-pattern-generation-like properties. Thus, oscillations of thelower limbs can be induced simply by vibrating the vastus lateralismuscle of the lower limb, by transcutaneous stimulation, and bystretching the hip. The neuromodulation system exploits the fact thatthe human spinal cord, in complete or incomplete SCI subjects, canreceive and interpret proprioceptive and somatosensory information thatcan be used to control the patterns of neuromuscular activity among themotor pools necessary to generate particular movements (e.g., standing,stepping, reaching, grasping, and the like). The neuromodulation systemdescribed herein facilitates and adapts the operation of the existingspinal circuitry that generates, for example, cyclic step-like movementsvia a combined approach of transcutaneous stimulation, physicaltraining, and, optionally, pharmacology.

Facilitating Stepping and Standing in Humans Following a ClinicallyComplete Lesion

Locomotion in mammals is attributed to intrinsic oscillating spinalneural networks capable of central pattern generation interacting withsensory information. These networks play critical roles in generatingthe timing of the complex postural and rhythmic motor patterns executedby motor neurons.

As indicated above, the neuromodulation system described herein caninvolve stimulation of one or more regions of the spinal cord incombination with locomotory activities. Spinal stimulation incombination with locomotor activity results in the modulation of theelectrophysiological properties of spinal circuits in the subject sothey are activated by Proprioceptive information derived from the regionof the subject where locomotor activity is to be facilitated. Further,spinal stimulation in combination with pharmacological agents andlocomotor activity results in the modulation of the electrophysiologicalproperties of spinal circuits in the subject so they are activated byproprioceptive information derived from the region of the subject wherelocomotor activity is to be facilitated.

Locomotor activity of the region of interest can be accomplished by anyof a number of methods known, for example, to physical therapists. Byway of illustration, individuals after severe SCI can generate standingand stepping patterns when provided with body weight support on atreadmill and manual assistance. During both stand and step training ofhuman subjects with SCI, the subjects can be placed on a treadmill in anupright position and suspended in a harness at the maximum load at whichknee buckling and trunk collapse can be avoided. Trainers positioned,for example, behind the subject and at each leg assist as needed inmaintaining proper limb kinematics and kinetics appropriate for eachspecific task. During bilateral standing, both legs can be loadedsimultaneously and extension can be the predominant muscular activationpattern, although co-activation of flexors can also occur. Additionally,or alternatively, during stepping the legs are loaded in an alternatingpattern and extensor and flexor activation patterns within each limbalso alternated as the legs moved from stance through swing. Afferentinput related to loading and stepping rate can influence these patterns,and training has been shown to improve these patterns and function inclinically complete SCI subjects.

Transcutaneous Stimulation of the Lumbosacral Spinal Cord

As indicated above, without being bound by a particular theory, it isbelieved that transcutaneous stimulation (e.g., over the thoracic spinalcord) in combination with physical training can facilitate recovery ofstepping and standing in human subjects following a complete SCI.

Spinal cord electrical stimulation has been successfully used in humansfor suppression of pain and spasticity. Recent efforts to optimizestimulation parameters have led to a number of research studies focusingon the benefits of transcutaneous spinal cord stimulation. The locationof the electrode and its stimulation parameters can be important indefining the motor response. Use of surface electrode(s), as describedherein, can facilitate selection or alteration of particular stimulationsites as well as the application of a wide variety of stimulationparameters.

The following non-limiting examples are offered for illustrativepurposes.

Example 1 Transcutaneous Electrical Stimulation of the Spinal Cord: ANoninvasive Tool for the Activation of Stepping Pattern Generators inHumans

A noninvasive method for activating the SN by means of transcutaneouselectrical spinal cord stimulation (tESCS) is demonstrated in thisExample. The method is based on our research that showed that a singledermal electric stimulus applied in the region of the T11-T12 vertebraecaused monosynaptic reflexes in the proximal and distal leg muscles inhealthy subjects and in patients with clinically complete (ASIA A)spinal cord injury. Taking into consideration that eESCS affects the SNthrough mono and polysynaptic reflexes, we suggested that noninvasivetESCS can be an effective way to neuromodulate the SN.

Experiment

We examined six healthy adult male subjects (students and staff of theVelikie Luki State Academy of Physical Education and Sports). They hadgiven their informed written consent to participate in the experiment.The experiment was approved by the Ethics Committee of the academy andmet the requirements of the Helsinki Declaration.

The subjects lay on a couch on their left side, with their feet placedon separate boards that were attached to a hook in the ceiling of theexperimental room with ropes, like swings. The right (upper) leg wassupported directly in the region of the shank. The left (lower) leg wasplaced in a rotating frame attached to a horizontal board. Under theseconditions, the subjects could move their legs through maximumamplitude: According to the instructions, the subjects lay quietly andneither counteracted nor facilitated the movements caused by electricalstimulation of the spinal cord.

The tESCS was performed using a KULON stimulator (St. Petersburg StateUniversity of Aerospace Instrumentation, St. Petersburg, Russia). Thestimulation was administered using a 2.5 cm round electrode (Lead-Lok,Sandpoint, United States) placed midline on the skin between the spinousprocesses of T11 and T12 as a cathode and two 5.0×10.2 cm rectangularplates made of conductive plastic (Ambu, Ballerup, Germany) placedsymmetrically on the skin over the iliac crests as anodes. The step-likemovements were evoked by a bipolar rectangular stimulus with a durationof 0.5 ms, filled with a carrier frequency of 10 kHz; the intensity ofstimulation ranged from 30 to 100 mA. The stimulation frequencies were1, 5, 10, 20, 30, and 40 Hz; the duration of exposure ranged from 10 to30 s. During the high-frequency stimulation within each stimulus, tESCSdid not cause pain even when the amplitude was increased to 100 mA ormore; allowing us to study in detail the dependence of the elicitedmovements on the amplitude and frequency of the stimulus.

The EMGs of the muscles of both legs (m. rectus femoris, m. bicepsfemoris, m. tibialis anterior, and m. gastrocnemius) were recorded bymeans of bipolar surface electrodes. EMG signals were recorded using anME 6000 16-channel telemetric electroneuromyograph (Mega Win, Finland).Flexion-extension movements in the knee joints were recorded using agoniometer.

The Qualisy video system (Sweden) was used to record the kinematicparameters of leg movements. Light-reflecting markers were attached tothe pivot points of the body, which coincided with the rotational axisin the shoulder, hip, knee, and ankle joints. The angular movements inthe hip joint were calculated from the location of markers on thelateral epicondyle of the humorous, trochanter, and lateral epicondyleof the femur. The markers that were attached to the trochanter, lateralepicondyle of the femur, and lateral ankle were used to describe themovements in the knee joint. The movements in the ankle joint wereestimated by means of the markers located on the lateral epicondyle ofthe femur, lateral ankle, and the big toe. The reconstruction ofmovements in one whole step cycle was performed by means of specialsoftware. In order to record the movements of the foot tip, the markerwas fixed on the big toe of the right foot.

The recording of EMG was synchronized with the recording of steppingkinematical parameters. The average cycle duration and the amplitudes ofangular movements were calculated from 10-12 cycles. The duration of astep cycle was calculated on the basis of the interval between twomaximum values of angular movements in the hip, knee, and ankle joints.The phase shift between the hip and knee joints was calculated from theinterval between the maximum values of angular movements in thesejoints.

The statistical treatment of the data was performed using a standardsoftware package.

Results

Transcutaneous electrical spinal cord stimulation with a frequency of5-40 Hz elicited involuntary leg movements in five out of six subjects.The threshold intensity of the stimulus that induced involuntarymovements was 50-60 mA and was dependent on the frequency ofstimulation. The tESCS at a frequency of 1 Hz caused reflex responses inthe leg muscles with a threshold of 70-80 mA (FIG. 8a ).

Original records of EMG responses in the muscles of the right leg to thetESCS at a frequency of 1 Hz and intensity of 75-100 mA are shown inFIG. 8. Increasing stimulus intensity resulted in an increase in theamplitude of responses. First, the hip muscles (m. rectus femoris and m.biceps femoris) were involved in the motor response; then, the shankmuscles (m. tibialis anterior and m. gastrocnemius) were involved (FIG.8b ). The response to each stimulus is composed of the earlymonosynaptic responses (the same is shown in Courtine, Harkema, Dy,Gerasimenko, and Dyhre-Poulsen, supra) with a latency period of about12-15 ms. Increasing stimulus intensity evoked responses in the bicepsfemoris muscle (flexor) with a latent period of a few tens ofmilliseconds, which were, apparently, polysynaptic. Thus, tESCS with alow frequency (1 Hz) elicited reflex responses in the leg muscles thatcontained mono and polysynaptic components.

Transcutaneous electrical spinal cord stimulation at frequencies in theentire range from 5 to 40 Hz caused step-like movements in five subjects(FIG. 9). There was some variability in the ability of tESCS to evokestep-like movements at different frequencies of stimulation. In twosubjects (R. and S.), step-like movements were evoked by tESCS at allthe test frequencies in the range 5-40 Hz; in subjects K and G., theywere recorded at frequencies of 5, 10, 20, and 30 Hz; and in subject B,they were recorded at frequencies of 5 and 30 Hz. The latent period ofthe starting of movements did not depend on the frequency of stimulationand was in the range of 0.2-2.5 s. The amplitude of movements insubjects S, G, and R at the beginning of stimulation gradually increasedto the maximum, and after its termination it gradually decreased. Insubjects K and V, the movements terminated against the background ofongoing tESCS, the duration of the stepping pattern was approximately10-20 s. In subjects R and S, the movements continued during the wholeperiod of stimulation and ended 2-4 s after its termination.

Pair wise comparison of the mean amplitudes of the movements of the hip,knee, and ankle joints calculated during the first and the last 15 s ofstimulation at each of the frequencies used allowed us to determine theprobability of the differences in the amplitudes of the inducedmovements at the beginning and at the end of the stimulation (see Table1, below). Two rows of probabilities for subject C, calculated on thebases of two experiments show the different direction of the changes inthe amplitudes at the beginning and end of stimulation. In the table,the cases when the amplitude of movements at the end of the stimulationwas significantly greater than in the beginning are boldfaced; the caseswhen the amplitude of movements at the end of the stimulation wassignificantly lower than in the beginning are italicized. According tothe data, the subjects were divided into two groups. In the first group(subjects R and S), step-like movements were evoked by the stimulationat the entire range of the frequencies studied (5-40 Hz), and theamplitude of movements, while growing at the beginning of stimulation,decayed after its termination. In the second group (subjects K and V),the movements were evoked with difficulty and with a limited set offrequencies. These differences could be related both to the individualcharacteristics of the electrical conductivity of the skin and tocharacteristics of the spinal connections.

The involuntary movements of the legs caused by tESCS fully compliedwith the characteristics of stepping movements (FIG. 10). Like voluntarystepping movements, the involuntary movements caused by tESCS surelycontain the alternating contractions of the similar muscles of the leftand right legs and the alternation of antagonist muscle activity in thehip and shin (rectus femoris and biceps femoris, gastrocnemius andtibial muscle of the shin). As clearly seen in the curves reflecting themotion of the hip and knee joints, the movements in these joints, bothvoluntary and evoked by tESCS, occurred with a phase shift (the motionin the knee ahead of the motion in the hip).

The table below shows the probability of similarity of the meanamplitudes of movements, measured in the first and the last 15 s duringtESCS. For subject S, two different cases of stimulation are shown.

TABLE 1 The Frequency of Stimulation Subject Joint 5 Hz 10 Hz 20 Hz 30Hz 40 Hz S. (1) H 0.08 0.16 0.20 0.005 0.1 Kn 0.003 0.26 0.41 0.030.0003 Ank 0.08 0.07 0.18 0.20 0.07 S. (2) H 0.01 0.0001 0.004 0.82 0.92Kn 0.04 0.0001 0.002 0.0004 0.12 Ank 0.002 0.0006 0.002 0.001 0.08 R. H0.07 0.05 0.14 0.27 0.007 Kn 0.0001 0.001 0.03 0.01 0.15 Ank 0.02 0.0080.003 0.47 0.68 K. H 0.99 0.002 Kn 0.03 0.008 Ank 0.21 0.001 B. H 0.030.16 0.27 0.68 Kn 0.12 0.06 0.04 0.02 Ank 0.05 0.99 0.15 0.001 G. H0.004 0.16 0.21 0.16 Kn 0.05 0.08 0.24 0.26 Ank 0.005 0.05 0.29 0.009Notes: H, hip joint; Kn, knee joint; Ank, ankle joint. The cases where p≤ 0.05 are boldfaced and italicized.

Stepping cycles in three joints of the right leg during voluntarystepping movements (FIG. 11a ) and movements elicited by tESCSreconstructed based on the kinematic analysis and the trajectory of thetip of the foot (the big toe) are shown in FIG. 11. In step-likemovements elicited by tESCS, as in voluntary stepping movements, thephase of carrying the leg forward and the phase of support during thebackward leg movements were distinct (FIGS. 11a, 11b ). During voluntarymovements, the patterns of the knee and ankle joints are more complexthan during the elicited movements. The coordination between the jointsduring the evoked movements is very different from that observed duringvoluntary movements (FIGS. 11c, 4d ). The same is true for the movementsof the distal region of the leg, resulting from the interaction ofmovements in all three joints, and recorded using a marker attached tothe big toe (FIG. 11f ). The trajectory of the terminal point involuntary movements looked like an ellipse (FIG. 11f ). The trajectoryof the terminal point in the movements elicited by tESCS may beconsidered a confluent ellipse, with the leg moving forward and backwardwithout significant vertical movements.

The frequency of step-like movements did not depend on the frequency ofstimulation. The average periods of step-like movements in subjects R,S, K, B, and G were 2.72±0.14, 2.39±0.55, 2.42±0.15, 3.22±0.85, and1.9±0.09 s, respectively.

As mentioned above, the pair wise comparison of the mean amplitudes ofthe movements in the hip, knee, and ankle joints calculated in the firstand the last 15 s of stimulation in different subjects, showed that,regardless of the stimulation frequency, the amplitude of movements mayeither increase or decrease significantly. At the beginning ofstimulation, there was a tendency for the amplitude of movements toincrease with increasing frequency of stimulation in all subjects forall joints (FIG. 12). However, at the end of stimulation, the amplitudeof movements was independent of the stimulation frequency. In alljoints, minimum movements were observed at a stimulation frequency of 5Hz (FIGS. 12b, 12d ). As an exception, only in one case, when subject S.was stimulated, the amplitude of movements in the hip joint increasedwith increasing stimulation frequency and the amplitude of movements inthe knee and ankle joints decreased with increasing frequency [FIG. 12;table 1, subject S. (1)]. The trajectory of movement of the big toe ofthis subject, reflecting the amplitude of the whole leg's movement, isshown in FIG. 12a . In this case, the amplitude of movement of the tipof the foot at stimulation frequencies of 10, 20, 30, and 40 Hz was,respectively, 15.0, 19.9, 15.3, and 16.4 times greater than at 5 Hz. Inthe case shown in FIG. 12b , it was, respectively, 3.5, 9.4, 11.3, and80.7 times greater than at 5 Hz. Thus, in this subject, with increasingfrequency of stimulation, the amplitude of leg movements did notdecrease in any of the cases; it was minimal at a frequency of 5 Hz.

Note that, in the cases shown in FIGS. 12b and 12d , an increase infrequency resulted in a significant increase in the amplitude ofmovements in the ankle joint. The possibility to control the movementsin the ankle joint via the frequency of stimulation was an advantage oftECS, unlike the ankle joint which was not modulated invibration-induced step-like movements. See Gorodnichev, Machueva,Pivovarova, Semenov, Ivanov, Savokhin, Edgerton, and Gerasimenko, supra.

DISCUSSION

Transcutaneous electrical stimulation of the lumbar enlargement maystrengthen the patterns of EMG activity in leg muscles in patients withcomplete or partial spinal cord lesions during assisted walkingmovements on a moving treadmill. However, voluntary step-like movementswere never successfully evoked by means of transcutaneous stimulation inthis category of patients before. It was observed that transcutaneouselectrical stimulation applied to the rostral segments of the lumbarenlargement (in the region of the T11-T12 vertebrae) elicitedinvoluntary step-like movements in healthy subjects with their legssuspended in a gravity-neutral position. This phenomenon was observed infive out of the six subjects studied. tESCS did not cause discomfort andwas easily tolerated by subjects when biphasic stimuli filled with acarrier frequency of 10 kHz which suppressed the sensitivity of painreceptors were used.

Reflex Nature of the Responses Evoked by tESCS

A single transcutaneous electrical stimulation in the region of theT11-T12 vertebrae causes responses in leg muscles with a latency periodcorresponding to monosynaptic reflexes. It was assumed that theseresponses are due to the activation of large-diameter dorsal rootafferents. The monosynaptic nature of these responses is confirmed bythe fact that vibration of muscle tendons or paired stimulationsuppresses the responses. We have previously shown that the responses tothe second stimulus were suppressed in rats during epidural stimulationand in healthy humans during paired tESCS with a delay between thestimuli of 50 ms. This refractory period excludes the possibility ofdirect activation of the motor neurons in the ventral horn or ventralroot activation. The monosynaptic nature of the responses was also shownduring vibration tests. It is well known that vibration suppressesmonosynaptic reflex pathways in homologous muscles. The suppression ofresponses caused by tESCS in shin muscles during the vibration of theAchilles tendon directly shows the monosynaptic nature of theseresponses. The similarity of modulations of the classical monosynapticH-reflex and reflex responses caused by tESCS during walking in healthysubjects and in patients with spinal cord injuries also supports themonosynaptic nature of the responses to transcutaneous stimulation. Inboth cases, the amplitude of modulation of the reflexes was proportionaland phase-dependent on the activation level of each muscle. All of theabove data indicate the identity of the H-reflex and reflex responsesinduced by tESCS.

In the flexor muscles affected by tESCS, polysynaptic reflexes weresometimes recorded in addition to the monosynaptic component (FIG. 8).Earlier, we recorded polysynaptic reflexes in the flexor the intact andspinal animals during the single epidural stimulation. Data suggeststhat tESCS can activate mono and polysynaptic neuronal networks.

Characteristics of Transcutaneous Stimulation Eliciting Step-LikeMovements

The previous experiments showed that the rostral segments of the lumbarspinal cord may play the role of triggers in initiating locomotormovements. In spinal patients and in spinal rats, step-like patterns ofEMG activity were evoked by epidural stimulation of the L2 segment. Inour experiments, we used transcutaneous electrical stimulation in theregion of T11-T12 vertebrae, which corresponds to the cutaneousprojection of the L2-L3 segments of the spinal cord. The electromagneticstimulation of this region in healthy subjects with their legs supportedexternally can initiate walking movements. Data are consistent with thecurrent concept on the structural and functional organization of the SNwith distributed pacemaking and pattern-generating systems, in which therostral lumbar segments of the spinal cord play the role of a trigger ofthe locomotor function.

The frequency of stimulation can be an important characteristic of themotor output. It was shown that step-like movements are evoked bystimulation frequencies in the range of 5-40 Hz. The amplitude ofstep-like movements induced by high-frequency stimulation (30-40 Hz) wasusually higher than that of the movements induced by low frequencystimulation (5 Hz), although the duration of the stepping cycle variedslightly. The fact that a wide range of frequencies can effectivelyinduce step-like movements is probably due to the functional state ofthe intact spinal cord and its pathways. For example, in spinalpatients, the effective frequency range for the initiation of step-likemovements using epidural stimulation was 30-40 Hz; in decerebrated cats,the frequency of 5 Hz was the most effective to elicit locomotion.

The intensity of transcutaneous electrical stimulation (50-80 mA) thatcauses step-like movements is approximately 10 times higher than theintensity of the epidural stimulation initiating walking movements inspinal patients. If the dorsal roots are the main target for both typesof stimulation, the current may be strong to activate them bytranscutaneous electrical stimulation. Thus, we conclude that thelocation, frequency, and intensity of stimulation can be the factorsthat determine the activation of the SN by tESCS.

The Origin of the Stepping Rhythm Evoked by tESCS

In most subjects, the involuntary step-like movements in the hip andknee joints were initiated by tESCS with a delay of 2-3 s after thestart of stimulation. Typically, the amplitude of movements in the hipand knee joints increased smoothly and gradually with the subsequentinvolvement of the ankle joint (FIG. 9). A similar character of theinitiation of involuntary step-like movements with gradual involvementof different motor pools of the leg muscles was also observed during thevibration of muscles and the epidural spinal cord stimulation. Thissuggests that transcutaneous electrical stimulation, as well as theepidural stimulation, affects the SN through the activation of thedorsal root afferents entering the spinal cord. In addition to thedorsal roots and dorsal columns, the direct stimulation of the spinalcord may also activate the pyramidal and reticulospinal tracts, ventralroots, motor neurons, dorsal horn, and sympathetic tracts. During thetESCS, the electric current spreads perpendicular to the spinal columnwith a high density under the paravertebral electrode. This stimulationapparently activates the dorsal roots immersed in the cerebrospinalfluid, but not the spinal cord neurons, which have a much lowerconductivity. In some embodiments, tESCS consequently involves inactivity the afferents of groups Ia and Ib with the largest diameterand, thus, the lowest threshold, then the afferents of the group II, andthe spinal interneurons mediating polysynaptic reflexes. The presence ofpolysynaptic components in the evoked potentials in the flexor muscles(FIG. 8) confirms that they participate in the SPG. Thus, we can saythat tESCS activates different spinal neuronal systems; however, thedorsal roots with their mono and polysynaptic projections to the motornuclei are the main ones among them. The contribution of mono andpolysynaptic components in the formation of the stepping rhythm causedby tESCS is not known.

In our studies, single pulse stimulation resulted in monosynapticreflexes in the majority of the leg muscles investigated. However, theelectromyographic trains evoked by continuous tESCS that inducedinvoluntary step-like movements were not formed by the amplitudemodulation of monosynaptic reflexes, as it was in spinal rats and duringthe spinal epidural stimulation of patients. Our data showed that theactivity within electromyographic trains was not stimulus-dependent;i.e., EMG trains did not consist of separate reflex responses. Similarstimulus-independent EMG trains were observed during involuntarymovements caused by spinal cord electromagnetic stimulation. Incontrast, the step-like movements evoked by the epidural spinalstimulation in rats and spinal patients were stimulus-dependent. In theextensor muscles, the EMG trains consisted mainly of monosynapticreflexes; in the flexor muscles, polysynaptic reflexes dominated in theEMG trains. It is not clear why single cutaneous and, respectively,single epidural spinal cord stimulation causes the same monosynapticreflexes in healthy subjects and spinal patients; however, continuousstimulation elicits their step-like movements through differentmechanisms. In healthy subjects, tESCS can increase the excitability ofthe neuronal locomotor network, being a trigger for its activation, inthe same way as in the case of vibration-induced step-like movements.

In this study, a new noninvasive access to locomotor spinal neuralnetworks in humans by means of tESCS has been described. A specialdesign of the stimulator, which generated bipolar pulses filled withhigh-frequency carrier, allowed us to stimulate the spinal cordrelatively painlessly and elicit involuntary step-like movements. Thefundamental importance of our study consists in the new data in favor ofthe existence of SN in humans that can coordinate stepping patterns andthe evidence of the possibility to engage this SN using noninvasiveeffects on the structures of the spinal cord. This increases prospectsfor widespread use of transcutaneous techniques in electrical spinalcord stimulation to study the mechanisms underlying the regulation ofthe locomotor behavior in healthy subjects and for the rehabilitationand motor recovery of patients after spinal cord injuries and afterother neuromotor dysfunctions.

Example 2 Voluntary Movements

We conducted a series of weekly training-testing sessions over a periodof about 18 weeks (FIG. 13). Each session from t₁-t₄ consisted ofstimulation at the level of T11, Co1, and the combination of the twosites with and without simultaneous voluntary effort to move the lowerlimb in a stepping motion. In addition, each session consisted ofpassively oscillating the limbs in a step-like fashion for three minuteswithout and three minutes with continuous stimulation. These passiveperturbations conditioned each individual. From t₂-t₄, the sameprocedures were followed but without the conditioning perturbations.This reduced level of perturbation was designed to maintain and sustaina plateau performance prior to the initiation of the drug phase of theintervention.

Over the 18-week period, six recording sessions (t₁-t₆; FIG. 13) wereperformed of detailed assessments reflecting quality of stepping-likemotions. In the first four weeks (4/5), subjects performed all fourtraining-testing sessions, whereas subject 5 only two training-testingsessions at three and four weeks.

To determine the effects of fEmc plus pcEmc the subjects weretrained-tested weekly over a period of 4 weeks (t₅-t₆). To determine thepotential for locomotor-like stepping all training and periodic testing(t₁-t₆) were performed in an apparatus designed to minimizegravitational effects (FIG. 14A).

Experimental Design

The subjects were tested while lying on their left side with the upperleg supported directly in the area of the shank and the lower leg placedon a rotating brace attached to a horizontal board supported by verticalropes secured to hooks in the ceiling. This arrangement allowed for thesuspended legs to move in an anterior-posterior plane in agravity-neutral position. For electrical stimulation at T11 and/or Co1 aspecific stimulation or stimulation waveform can be and was used thatdoes not elicit pain, even when used at energies required totranscutaneously reach the spinal cord. This stimulation can include abiphasic signal and an overlapping high frequency pulse. Painlesstranscutaneous electrical stimulation (pcEmc) was delivered using a 2.5cm round electrode (Lead Lok, Sandpoint, United States) placed midlineon the skin between spinous processes T11-T12 (simply T11) or overcoccyx 1 (Co1) as a cathode and two 5.0×10.2 cm² rectangular plates madeof conductive plastic (Ambu, Ballerup, Germany) placed symmetrically onthe skin over the iliac crests as anodes.

Kinematics and EMG Recordings.

Leg movements were evoked by monopolar rectangular stimuli (1 msduration) filled with a carrier frequency of 10 kHz and at an intensityranging from 80 to 180 mA. The stimulation frequency was 30 Hz at T11and 5 Hz at Co1. The duration of continuous exposure ranged from 10 to180 s. Bipolar surface electrodes were placed bilaterally on the soleus,medial gastrocnemius (MG), tibialis anterior (TA), medial hamstring(HM), and vastus lateralis (VL) muscles. EMG signals were amplifieddifferentially (bandwidth of 10 Hz to 10 kHz) and acquired at 10 KHzusing a 16-channel hard-wired A/D board and customized LabVIEW software(National Instruments, Austin, Tex.) acquisition program. To minimizeartifacts from the stimulation, the EMG signals were passed through aband-pass filter using a six-order band-pass Butterworth filter (30-200Hz). The filtered EMG signals were analyzed off-line to compute theamplitude, duration, and timing of individual bursts.

Angular displacements at hip and knee joints in both legs were recordedwith goniometers. Two procedural sequences were followed for eachsubject on a given day of testing. Each subject was tested weekly up toeighteen weeks. The subjects had access to visual feedback via a mirrorplaced so that movement of the legs could be observed.

Conditioning Procedures.

The conditioning procedure consisted of imposing passive movement of thelegs in an oscillatory pattern for three minutes (conditioning) and thenimposing a passive movement plus stimulation at T11, Co1 or T11+Co1simultaneously for three minutes. The total time for each testingsession was about 45 minutes. The same protocol was followed once a weekfor the first and last four weeks. Whether the conditioning treatmentonly within a single training session could facilitate the ability togenerate knee oscillations without and with stimulation at t₆ (FIGS.19A-19D) was also tested.

Drug Treatment.

All subjects were informed that they would receive either a placebo orthe serotoninergic agonist buspirone. All subjects were given buspirone7.5 mg orally twice daily for the last 4 weeks (FIG. 13 and FIG. 15B).

Clinical Statement of the Patients.

The University of California, Los Angeles Institutional Review Boardapproved all procedures. Subjects were enrolled based on the enrollmentcriteria of traumatic cervical or thoracic injury, AIS B, greater than 1year from injury, and stable motor function as documented by sequentialclinical exams. The clinical profiles of the subjects upon enrollmentinto this study are as follows: Subject 1 (S1) is a 42 year old male whosuffered a T3-T4 SCI after a steer wrestling accident and was 24 monthsfrom initial injury. S2 is a 20 year old male who suffered a C5-C6 SCIsustained during a football game and was 36 months from initial injury;S3 is a 20 year old male who suffered a C6 SCI after a motor vehicleaccident and was 36 months from initial injury; S4 is a 19 year old malewho suffered a C7 SCI during a swimming accident and was 24 months frominjury; and S5 is a 56 year old male who suffered a T3-T4 SCI after abicycle accident and was 72 months from injury. Magnetic resonanceimaging was obtained in all subjects to confirm the location and extentof the injury (FIG. 8).

Electrophysiological Assessment of the Patients.

Transcranial magnetic motor evoked potential (MEP) tests and lowerextremity somatosensory evoked potential (SEP) tests were obtained inall subjects. For MEP, all subjects demonstrated absence of lowerextremity muscle activity upon stimulation at the cortical level and noconduction was observed through the level of impairment. For SEP,subjects demonstrated absence of cortical peaks bilaterally with noevidence of conduction across the known spinal cord injury.

Additionally, the ability to control the leg muscles voluntarily wastested in all subjects while in a supine position. Flexor (TA) EMG wasrecorded during dorsiflexion and extensor (MG and soleus) EMG duringplantarflexion and evoked potentials were recorded in the leg muscles inresponse to pcEmc at T11-T12 during attempts to maximally dorsiflex orplantarflex. In uninjured subjects, the amplitudes of the muscle evokedpotentials were higher with a voluntary contraction compared to thoserecorded at rest (FIG. 21A). In all SCI subjects there was minimal EMGactivity during these attempts and the amplitude of the evokedpotentials were similar to those recorded at rest (FIGS. 21B-21F). Intwo subjects (S2 and S5) the intent to dorsiflex surprisingly led to anincrease in the amplitude of the evoked potentials in the extensor, butnot the flexor, muscles (FIGS. 21C and 21F), indicating aberrantneuronal (or neuromuscular) connections. These electrophysiologicalresults indicate that voluntary control of the leg muscles was absent inthese patients. These electrophysiological assessments are consistentwith the morphological assessments derived from MRI (FIG. 20).

Assessment of Voluntary Movements.

The ability to facilitate voluntarily generated locomotor-like movementsduring spinal cord pcEmc when the legs were placed in a gravity-neutralposition was determined. After instructing each subject to oscillate thelimbs as if stepping, the subject was asked to relax for a period of15-20 sec before we initiated pcEmc with the cathode at the T11 and/orCo1 vertebral level. Then, the subject was asked to attempt tovoluntarily oscillate the legs in the presence at T11, Co1, or T11+Co1.In the first Pre-Train session without pcEmc, initially none of thesubjects could voluntarily initiate or influence rhythmic locomotor-likelimb movements and rhythmic EMG activity of the leg muscles. Aftertreatment with buspirone (Post-Drug), all subjects improved ingenerating oscillatory, locomotor-like movements with only a voluntaryeffort and the robustness of the movement was similar when voluntaryeffort was combined with pcEmc at T11+Co1 (FIG. 15C).

Statistical Analyses.

All statistics were performed in SPSS v. 19 (IBM) with base, regression,advanced models, and categories packages. Non-linear PCA (NL-PCA) wasimplemented using the CATPCA command with appropriate link functions toaccommodate non-linear and non-normal distributional features for eachvariable. PC (object) scores were extracted across all endpoints,subjects, and levels of the repeated measures. PC retention wasdetermined by the eigenvalue >1 rule, and the face validity of PCloading patterns. PC1 scores then were carried forward as the principaloutcomes for assessing the impact of the experimental manipulations by3-way repeated measures ANOVA (GLM command), with each subject servingas their own control. Significant interactions were followed up byinteraction graphing with assessment specific differences by one-wayANOVA and Tukey's post-hoc. Significance was assessed at P<0.05.

PcEmc activation of locomotor neuronal networks was assessed. During thefirst testing session (t₁) some rhythmic hip and knee movements andcorresponding EMG activity were induced during pcEmc without anyvoluntary effort when the legs were placed in a gravity-neutral position(FIG. 14A). Examples of the relative effects of spinal cord stimulationwith the electrodes placed at T11 (30 Hz) or Co1 (5 Hz) vertebral levelsand the combination of stimulation from both sites simultaneously onthese leg movements in the same subject during Pre-Train (t₁) andPost-Drug (t₆) are illustrated in FIG. 14C and FIG. 14D (same subject att₁ and t₆ under each stimulation condition), respectively. The meanamplitudes of the angular movements at the hip and knee joints duringvoluntary efforts with and without stimulation were generally greaterPost-Drug than Pre-Train (FIG. 14B). In addition, the EMG bursts weregenerally more robust Post-Drug than Pre-Train (FIG. 14C vs. FIG. 14D).

Also, voluntary control of leg movements enabled by pcEmc and trainingwas assessed. Initially (t₁) none of the subjects could voluntarilyinitiate rhythmic locomotor-like limb movements with any detectablerhythmic EMG activity of the leg muscles (FIG. 15A). On the first day oftesting (t₁), there was more than a two-fold increase (P<0.05) in theknee angle oscillatory range with a combination of voluntary effort andpcEmc compared to a voluntary effort alone or pcEmc alone (FIG. 15B;t₁). Some movement occurred at t₁ with voluntary effort alone, but thiswas without any EMG oscillatory responses and occurred due to thesubjects mechanically transferring trunk and hip motion to the lowerlimbs. At the end of the four weeks of training with pcEmc (t₂), thesubjects had not recovered a significant level of knee movement during avoluntary effort with or without stimulation (FIG. 15B).

Relative effectiveness of voluntary effort compared to voluntary effortplus pcEmc changed at the Post-Drug phase (t₆). At the end of the drugphase, the overall performance during voluntary effort alone was aseffective as voluntary effort plus stimulation (FIG. 15B). The averagerange of voluntary movement at the knee Post-Drug (t₆) was two-foldgreater than Pre-Drug (t₂) and six-fold greater than at the initial test(t₁) (FIG. 15B). These mean differences (FIG. 15C) are even moreimpressive when considering the variation in the responsiveness to pcEmcas a function of subject specificity and the site of pcEmc in theresponse to fEmc treatment (FIGS. 16A-16C). For example, the angulardisplacement for S1 was lower Post-Drug (t₆) with the combination ofvoluntary effort plus stimulation at T11 vs. voluntary effort alone.This occurred at each of the stimulation sites for this subject. Thisalso occurred with subject 4 with the stimulation sites involving T11and T11 plus Co1.

Although the effects of pcEmc at different spinal levels and atdifferent phases of the interventions varied among subjects, non-linearprincipal component analysis (NL-PCA) revealed a consistent linkagepattern between the hip and knee angular displacements (FIGS. 16B-16C).Based on PC1 there was an emergence of organized oscillations inresponse to pcEmc, fEmc, and training.

To determine whether there was an additive effect of fEmc to thatobserved with pcEmc and training further test were performed. An exampleof one subject's hip and knee displacements and the EMG of selectedmuscles at t₁ vs. t₅ is shown in FIG. 17A. Clear rhythmic EMG burstingand oscillatory movement of the hip and knee at t₅ was compared to t₁.After two weeks of pcEmc+fEmc treatment (FIG. 17B; t₅), a significantfacilitation in the mean voluntary performance (without pcEmc) oflocomotor-like movements and this effect continued after two more weeksof pcEmc plus fEmc treatment (FIG. 17B; t₆) was observed. Thesestatistical comparisons suggest that 1) the magnitude of the range inknee oscillations was increased with voluntary effort plus pcEmc at t₁even within the first test session (FIG. 15B and FIG. 16C), 2) there wasa further increase in the range of these oscillations after four weeksof fEmc (t₆) (FIG. 15C and FIG. 16C), and 3) there was notablesubject-specificity for the stimulation site that evoked the greatestresponses to the interventions at all phases (FIGS. 16A-16C).

Clinical assessment according to the ASIA impairment scale (AIS) isconsistent with improvement of motor function after pcEmc+fEmc treatmentin all five subjects (FIG. 17C). No clinical movement (score of 0) wasobserved in any of the lower extremity joints at the Pre-Train phase(t₁). An average improvement of 7 points was observed in this cohortduring the Post-Drug (t₆) condition. In the presence of theseinterventions this would be equivalent to the subjects beingreclassified from AIS B to C.

Further, modulation of evoked potentials during voluntary efforts wasassessed. While monitoring varying physiological states of the spinalcircuits in vivo while performing motor tasks in animals and humansubjects, we demonstrated electrophysiological evidence of supraspinallymediated neuromodulation of the spinal circuitry in the presentsubjects. To assess these interactions we recorded spinally evokedpotentials generated in the TA and MG muscles when the subject was lyingin the gravity-neutral apparatus. We asked the subject to swing the legforward (flex) and backward (extend; shaded areas in FIG. 18A) and thenforward again in the presence of continuous stimulation.

FIGS. 18B and 18C show examples of the malleability of thebrain-to-muscle connections in response to different pcEmc stimuli inthe presence and absence of voluntary efforts to flex or extend thelower limbs. Also, by testing this brain-spinal connectivity whenstimulating at the level of Co1 and/or T11, we observed clear inhibitoryand excitatory patterns of responses in the TA and MG motor poolsdepending on the stimulation site. When stimulating at Co1 we observed aclear facilitation of the TA motor pool mediated by voluntary effort,whereas the MG motor pool was slightly suppressed with voluntary effort.

In some embodiments, a consistent delay of the response of approximately2 ms in the MG was observed when there was a voluntary effort to extendthe lower limb (FIG. 18B). The complexity of the functional brain-spinalconnectivity is illustrated further by the suppression of any responsein the MG when T11 and Co1 were stimulated simultaneously with orwithout voluntary effort and an evoked potential only occurring in theTA when there was a voluntary effort to extend (FIG. 18B). Theseinteractive effects of stimulation at different sites with and withoutvoluntary efforts are summarized graphically in FIG. 18D.

In other embodiments, a combination of pcEmc, fEmc, and training canopen new functional connections among brain-spinal cord networks andthat these functional connections are highly dynamic and interactive.Given that significant improvements in motor function can continue toemerge three years after the implantation of epidural electrodes and theresponses of individual motor pools to the newly emerged descendingvoluntary input to the spinal circuitry to pcEmc at differentfrequencies and at different sites along the spinal cord, interactionsof each of these modulatory components are highly interdependent.

Further still, proprioceptive conditioning effects on voluntary legmovements were assessed. To show that the properties of thesebrain-spinal cord networks (e.g., circuitry plasticity over a period ofweeks) could be modulated more acutely, at t₆ we tested whether theproprioceptive-induced conditioning treatment within a single trainingsession could facilitate the ability to generate knee oscillations witha voluntary effort alone or with a voluntary effort plus stimulation.The conditioning treatment consisted of imposing passive, continuous,anterior-posterior limb movements in an oscillatory step-like pattern(about 20 cycles/min) for three minutes without stimulation followed bythree minutes with stimulation either at T11, Co1, or T11+Co1 with thesubject's legs in a gravity-neutral apparatus.

Changes in the EMG and kinematics output over the progression of asingle three-minute conditioning session without pcEmc and then withpcEmc at T11 were followed. When we compared the EMG and kinematicsresponses during the first 30 seconds and the final 30 seconds of thethree-minute conditioning bout, a gradual increase in EMG amplitudeduring the initial 30 seconds and remained elevated up to the final 30seconds with little or no change in the kinematics with and withoutpcEmc (FIG. 19A) was observed. An important difference was that thelevel of neuromodulation during conditioning combined with pcEmc wassignificantly greater than conditioning without pcEmc. Improvedcoordination of the motor pools for the knee and ankle flexors andextensors over these different 30-second time periods under eachcondition noted above also were evident (FIG. 19B).

In some embodiments, the systems and methods described herein can afterthe completion of a three-minute conditioning period combined with T11pcEmc increase the level of activation of the motor pools associatedwith the flexor and extensor muscles at the hip, knee, and ankle and thehip and knee displacement increased, e.g., significantly, with voluntaryeffort alone and with voluntary effort plus pcEmc beyond that observedprior to the procedure (FIGS. 19C-19D). This effect was greater, e.g.,significantly, with voluntary effort plus pcEmc than with voluntaryeffort alone (FIG. 19D). Further, levels, e.g., significant, ofreciprocal modulation in concert with elevated EMG amplitudes wereobserved in the presence of stimulation (FIG. 19B).

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the devices, techniquesand methods disclosed herein elucidate representative embodiments thatfunction well in the practice of the present disclosure. However, thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsthat are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The use of the term or in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects those of ordinary skill in the art toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference in their entirety.

Further, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A neuromodulation system comprising: a processor; a signalgenerator; and at least one electrode; wherein the processor, incooperation with the signal generator and the at least one electrode areconfigured to deliver a first transcutaneous stimulation to a spinalcord or brainstem of a mammal, the stimulation including firstparameters defining a signal and an overlapping high frequency pulse,the first transcutaneous stimulation configured to induce voluntarymovement in the mammal, the system further comprising one or moresensors configured to measure a response of the mammal related to thefirst transcutaneous stimulation, wherein the processor is configured todetermine a second transcutaneous stimulation having second parametersby performing a Gaussian process optimization or a dueling banditmachine learning algorithm or process that is configured to use, inpart, an association between the measured response and the firstparameters of the first transcutaneous stimulation.
 2. Theneuromodulation system of claim 1, wherein the mammal is a human.
 3. Theneuromodulation system of claim 1, wherein the voluntary movement is ofa foot, a toe, a leg, an arm, a hand, a finger, a waist or a combinationthereof.
 4. The neuromodulation system of claim 1, wherein the voluntarymovement comprises at least one of standing, stepping, a walking motorpattern, sitting down, laying down, reaching, grasping, pulling andpushing, swallowing and chewing, breathing, and coughing.
 5. Theneuromodulation system of claim 1, wherein the signal is a 0.5-100 Hzsignal.
 6. The neuromodulation system of claim 5, wherein the signal isdelivered at 0.5-200 mA.
 7. The neuromodulation system of claim 1,wherein the overlapping high frequency pulse is a 10 kHz pulse.
 8. Theneuromodulation system of claim 1, wherein the overlapping highfrequency pulse is a 5 kHz pulse.
 9. The neuromodulation system of claim1, wherein the first transcutaneous stimulation is applied over acervical portion of the spinal cord or the brainstem.
 10. Theneuromodulation system of claim 1, wherein the first transcutaneousstimulation is applied paraspinally over at least one of a lumbarportion, a lumbosacral portion, and a sacral portion of the spinal cord.11. The neuromodulation system of claim 1, wherein the firsttranscutaneous stimulation is applied over a T11-T12 vertebrae.
 12. Theneuromodulation system of claim 1, wherein the mammal has aneurodegenerative brain injury.
 13. The neuromodulation system of claim12, wherein the neurodegenerative brain injury is associated with acondition selected from the group consisting of Parkinson's disease,Huntington's disease, Alzheimer's, ischemia, stroke, dystonia,amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), orcerebral palsy.
 14. A method of inducing a voluntary movement in amammal with a spinal injury, the method comprising: delivering, using atranscutaneous neuromodulation system, a first transcutaneousstimulation to a spinal cord or brainstem of the mammal, the firsttranscutaneous stimulation including first parameters defining a signaland an overlapping high frequency pulse; measuring, via a sensor, aresponse of the mammal related to the first transcutaneous stimulation;determining a second transcutaneous stimulation including secondparameters using a processor by performing a Gaussian processoptimization or a dueling bandit machine learning algorithm or processthat is configured to use, in part, an association between the measuredresponse and the first parameters of the first transcutaneousstimulation, and applying the second transcutaneous stimulation to thespinal cord or brainstem of the mammal using the transcutaneousneuromodulation system.
 15. The method of claim 14, wherein thetranscutaneous neuromodulation system further includes: a signalgenerator; and at least one electrode.
 16. The method of claim 14,wherein the signal is a 0.5-100 Hz signal.
 17. The method of claim 16,wherein the signal is delivered at 0.5-200 mA.
 18. The method of claim14, wherein the overlapping high frequency pulse is a 10 kHz pulse. 19.The method of claim 14, wherein the overlapping high frequency pulse isa 5 kHz pulse.
 20. The method of claim 14, wherein the voluntarymovement is of a leg, a foot, a toe, an arm, a hand, a finger, a leg, awaist or a combination thereof.